Aim 23(3) 121-134.pdf

A review of myofascial pain and fibromyalgia– factors that promote their persistenceAbstract
Chronic muscle pain (myalgia) is a common problem throughout the world. Seemingly simple, it is actually
a difficult problem for the clinician interested in determining the aetiology of the pain, as well as in managing
the pain. The two common muscle pain conditions are fibromyalgia and myofascial pain syndrome.
Fibromyalgia is a chronic, widespread muscle tenderness syndrome, associated with central sensitisation. It
is often accompanied by chronic sleep disturbance and fatigue, visceral pain syndromes like irritable bowel
syndrome and interstitial cystitis. Myofascial pain syndrome is an overuse or muscle stress syndrome
characterised by the presence of trigger points in muscle. The problem these syndromes pose lies not in
making the diagnosis of muscle pain. Rather, it is the need to identify the underlying cause(s) of persistent or
chronic muscle pain in order to develop a specific treatment plan. Chronic myalgia may not improve until the
underlying precipitating or perpetuating factor(s) are themselves managed. Precipitating or perpetuating
causes of chronic myalgia include structural or mechanical causes like scoliosis, localised joint hypomobility,
or generalised or local joint laxity; and metabolic factors like depleted tissue iron stores, hypothyroidism or
Vitamin D deficiency. Sometimes, correction of an underlying cause of myalgia is all that is needed to
KeywordsMyalgia, hypothyroidism, trigger points, referred pain, fibromyalgia, myofascial pain syndrome.Introduction to fibromyalgia and myofascial
limb, in the same region, in the body wall, or in a
pain
visceral organ. Referred pain tends to be segmental,
Myalgia is muscle pain or pain of muscular origin,
so that referred pain patterns are usually located in
irrespective of cause. There are two major types of
sites innervated by adjacent or nearby spinal cord
non-inflammatory myalgia that are commonly
segments. Hence, trigger points in the posterior
diagnosed. One is fibromyalgia (FMS). It is a
shoulder muscles like the supraspinatus and
syndrome in which there is chronic, widespread
infraspinatus muscles that are innervated by C5 refer
muscle tenderness as a result of central sensitisation.
pain to the shoulder (C4-5 dermatomes) and the arm
FMS is denoted as primary when there is no co-
and hand (C5-6-7-8 dermatomes). Likewise, upper
existent disease that causes widespread muscle pain.
cervical spine muscle trigger points, that have an
FMS is considered secondary when myalgia is co-
input into the descending (caudal) trigeminal nucleus,
morbid with other disorders. Myofascial pain
refer pain to the head, because the meninges and the
syndrome (MPS), the other common muscle pain
face are innervated by the trigeminal nerve.
syndrome, is associated with discrete taut bands of
Myalgia can be a primary chronic pain state in
hardened muscle that contain regions of exquisite
muscle tenderness. It, too, may be a central
abnormalities that are specific for FMS or MPS.
hypersensitivity syndrome, but little research has
Myalgia that lasts for three months or longer is
been done on this point in MPS. A striking property
considered chronic. It can be a disabling generalised
of MPS painful regions is that they generate referred
pain that is often associated with disturbed rest and
pain that is felt in a different, usually distal, site. The
debilitating fatigue. Treatment success may be
site of referred pain perception can be in the same
limited. Treatment of co-morbid myalgia can also
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be difficult, especially if a treatable cause of a co-
underlying, etiological or co-morbid disorders are
applicable to both syndromes. There is always the
possibility that muscle pain associated with exercise
tenderness, but beyond that common phenomenon
intolerance and fatigue can be due to a problem that
they differ and form two distinct entities. FMS is a
is neither FMS or MPS, such as that seen with a
syndrome (not a disease) of central sensitisation and
mutation in the cytochrome b gene of mitochondrial
musculoskeletal tenderness and pain. MPS is also a
deficiency, perhaps myoadenylate deaminase
syndrome. It is the result of a local muscle metabolic
deficiency, or hypothyroidism. Thus, the diagnosis of
stress that is thought to produce an energy crisis that
FMS or MPS based on the presence of muscle pain,
does not support a specific muscle action. It may
fatigue, and exercise intolerance, and the physical
develop after one maximal contraction or excessive
findings of tenderness or of myofascial trigger points,
eccentric contraction in an untrained muscle.1 It is
is not sufficient to give primary consideration solely
associated with a discrete linear band-like hardness
or tautness (trigger points) within one or more
muscles, leading to the release of nociceptive
Fibromyalgia
substances such as substance P, potassium, and
histamine that activate peripheral nociceptive
FMS is a chronic, widespread myalgia that by
receptors and dorsal horn nociceptive neurons.
definition involves the body above and below the
Biochemical changes at the heart of the trigger zone
waist, and to the right and left sides of the midline,
(elevated levels of calcitonin gene-related peptide,
such that three or four quarters of the body are
of substance P, norepinephrine, and tumour necrosis
involved. Chronic and widespread pain of muscle
factor-1D, and of interleukin 1 and 6, and a low pH
origin are reflected in the criteria for diagnosis
of 3.0 to 4.0) have been identified by Shah et al.2 A
region of the taut band is exquisitely tender and can
Rheumatology (ACR).4 Using the ACR criteria,
refer pain to another, usually distal, region. Sleep
3.5% of women and 0.5% of men in the United
disturbance in addition to pain will more likely result
States have been estimated to have FMS. The ACR
in the diagnosis of FMS. Exercise intolerance can
criteria, intended to provide a uniform definition of
be seen with either FMS or MPS. Many cases of
fibromyalgia for research studies, require that: 1)
FMS are in fact cases of MPS that have been
symptoms have been present for at least three
misdiagnosed as a result of poor muscle palpation
months; and 2) 11 sites of a specified 18 sites be
techniques that miss the presence of taut bands and
tender (Table 1). Diagnosis of FMS in clinical
referred pain. Nevertheless, the comments regarding
practice was never intended to be as strict as that
required for research purposes. Chronic and
widespread muscular pain are still required to make
the diagnosis, but the extent of muscle tenderness
Table 1 The tender points used to diagnose fibromyalgia
may vary over time, and there may be far fewer
than 11 tender sites found on examination at any
given time. Chronic symptoms including widespread
musculoskeletal pain syndromes with a specificity
of 81% and a sensitivity of 88%.4 However, they
do not distinguish FMS from chronic, widespread
MPS or any other chronic condition where there is
upper outer quadrant of the gluteal muscles
widespread muscle tenderness, since tenderness is
the sole significant physical finding specified in the
medial knee above the joint line (medial fat pad or
ACR criteria. In fact, MPS is the most common
condition that must be considered in the differential
Each point is examined bilaterally for a total of 18 points.
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Any condition associated with myofascial trigger
with pelvic floor MPS syndromes. Depression may
points will produce tenderness to palpation. Such
occur in as many as 30% of FMS patients, but is also
conditions include nutritional deficiency states such
said to be no more common in FMS than in the
as iron insufficiency, vitamin B12 deficiency,
hormonal disorders eg hypothyroidism, and trauma
eg cervical strain injury (‘whiplash’). Consequently,
the physical examination performed for the evaluation
Fibromyalgia has been extensively studied to try to
of myalgia must include palpation for the taut bands
identify an underlying physiological or biochemical
of myofascial trigger points (see below), including an
basis to explain the fatigue and the muscle tenderness.
attempt to elicit referred pain, as well as for the tender
Evidence has accumulated that tenderness in FMS is
points of FMS. A comprehensive medical evaluation
related to central sensitisation with amplification of
is also indicated in order to identify conditions in
nociception, resulting in a broad array of stimuli
which diffuse myalgia occurs secondarily. A localised
perceived as being more painful among FMS patients
or regional muscular pain syndrome such as that
than they are in control populations.8-11 This is a
associated with whiplash is not FMS when there is no
fundamental abnormality that is very likely related
widespread muscle pain that occurs above and below
to the cause of fibromyalgia. Increased substance P in
the waist. Even when there is widespread pain, it
cerebral spinal fluid may be relevant to the generalised
hypersensitivity (which includes ‘hypervigilance’)
The acceptance of the ACR criteria fostered a
seen in FMS. Sleep disturbance, with lack of sustained
virtual explosion in the publication of research studies
stage three and four sleep and intrusion of alpha
on the nature of fibromyalgia, even though the
activity into delta-wave sleep, has been reported in
diagnostic criteria were criticised as invalid and based
FMS, and patients complain of non-restorative, non-
on circular reasoning. Nevertheless, despite the
refreshing sleep. Alterations in cardiovascular
criticism, the criteria serve a useful purpose as
autonomic nervous system function lead to orthostatic
similarly established criteria do in other chronic or
hypotension, or neurally-mediated orthostatic
recurring pain states that lack objective markers,
tachycardia,12 further aggravating fatigue and impaired
such as non-specific low back pain and migraine
ability to function. Neuroendocrine abnormalities in
headache without aura. The clinical diagnosis of
the hypothalamic-pituitary-adrenal system, and growth
FMS continues to be based on the history and
hormone deficiency, are hormonal deficiency states
physical examination. Laboratory tests and imaging
that may tie together the symptoms of fatigue, pain and
procedures are not useful for making a positive
sleep and mood disturbances.13 Growth hormone is
diagnosis, but are required to evaluate the patient
secreted during sleep; the deficiency of serotonin in
for co-morbid conditions or to identify other reasons
FMS leads to sleep disturbances and possibly to the
decrease in growth hormone secretion. Interleukin-8
levels are increased in FMS patients and related to
pain intensity, suggesting a role for cytokines in the
FMS is above all else a chronic muscular pain
syndrome,6 but it is associated with a number of other
symptoms that include sleep disturbance and fatigue,
favourable than initially thought. Symptoms may
headache, morning stiffness, irritable bowel
persist for years, but patients either learn to cope
syndrome (IBS), interstitial cystitis (IC), dyspareunia,
with the chronic pain, or the pain does not progress.
and mood disturbance. Some of these symptoms are
A substantial percentage of FMS patients reported
manifestations of referred muscle pain from
some lessening of pain over the years, even though
myofascial trigger points (headache, dyspareunia,
they were still symptomatic. Functioning improves
morning stiffness), and others, like IBS and IC are
over the years, particularly in the older population
viscerosomatic pain syndromes,7 that occur more
(55 to 64 years old), possibly because of more
frequently in persons with FMS (up to 70% in FMS
effective coping skills. Symptoms decrease with age,
patients). The viscerosomatic syndromes are by no
and older patients have less pain, depression, illness
means unique to FMS, and are usually associated
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for the use of tramadol, selective serotonin reuptake
Treatment of fibromyalgia has included a wide
inhibitors, selective serotonin and norepinephrine
variety of pharmacological, nutritional, hormonal,
reuptake inhibitors, and certain anticonvulsant drugs.
behavioural, cognitive, exercise and physical
Moderate evidence also exists for the efficacy of
modalities. Extensive experience in the use of
strength training, acupuncture, hypnotherapy,
antidepressants in the treatment of FMS has
biofeedback, massage and warm water baths. Many
accumulated over the years. Amitriptyline potentiates
commonly used treatments were found not to have
the analgesic effect of opioids, and it, as well as other
tricyclic antidepressants and the new antidepressants,
venlafaxine and duloxetine, inhibit the re-uptake of
Myofascial Pain Syndrome
serotonin and norepinephrine at neuronal terminals.
Amitriptyline at 25-50mg at bedtime produces initial
MPS is a muscular pain syndrome that arises from a
improvement that has not been shown to be sustained
primary dysfunction in muscle and yet is associated
more than six months.15 The new serotonin and
with central sensitisation and a segmental spread
norepinephrine reuptake inhibitor duloxetine, and
within the spinal cord to give rise to the phenomenon
the new anticonvulsant pregabalin have both been
of referred pain, or pain that is felt at a distance.18
shown to be effective in reducing the symptoms of
The clinical picture of MPS is one of musculoskeletal
FMS. Antidepressant treatment improves sleep,
pain, limited mobility, weakness and referred pain.19
fatigue, pain and wellbeing, but does not change
There may be clumsiness and in-coordination as
tender point counts. A problem with the clinical trials
well. The specifics of the MPS in a given individual
of tricyclic antidepressant therapy is that they are of
are dependent on which muscles are involved.
short duration. Only one study lasted 6.5 months,
Involvement of the muscles of the head, neck and
and it showed no greater effectiveness for
shoulders gives rise to headache and neck and
shoulder pain. Involvement of the pelvic floor
muscles causes pain referred to the viscera (bowel,
hormone (GH) replacement in the subset of about
bladder and genitourinary tract organs). Hamstring
one in three FMS patients who have a demonstrated
muscle involvement can impair sitting because of
deficiency of GH or insulin-growth-factor-1. The
pain felt at the ischial tuberosity, and can also cause
treatment is expensive, and is of benefit only as long
pain that is felt behind the knee. Pain can be felt at the
as the replacement is given. Thyroid hormone
site of the muscle dysfunction, called the Myofascial
replacement is likewise beneficial in those patients
Trigger Point (MTrP), and also in the region of
who have demonstrated hypothyroidism, but there
referred pain. For example, trigger points in the
are no data that suggest that hypothyroidism is more
subscapularis muscle can cause both local shoulder
common in FMS than in the general population.
Graded, progressive exercise programmes provide
The features of the trigger point itself comprise
both short and long-term improvement in FMS.
both a taut band and pain. This duality of the MTrP
Cognitive therapy is effective when combined with
emphasises the two main characteristics of the MTrP:
exercise. Supplements such as guaiphenesin and
a motor or architectural abnormality and a painful
sensory dysfunction. The motor abnormality is an
magnesium, and S-adenosylmethionine (SAMe) are
abnormal hardness in the muscle that is felt on
commonly used, but there are few data to show that
palpation of the muscle. One or several bands within
they are effective in the management of FMS.16 A
the muscle are felt to be hard, stiff or taut. The usual
committee of the American Pain Society recently
description is that of a taut band. It is discrete within
reviewed the evidence for effectiveness of currently
the muscle, and generally extends the full length of
available treatment recommended for fibromyalgia.17
the muscle between tendons or tendinous bands (like
They found strong evidence to support the use of low
the inscription bands in the rectus abdominis or
dose tricyclic antidepressants and cylcobenzaprine,
hamstring muscles). The entire muscle is not hard
cardiovascular exercise, cognitive behavioural therapy,
or cramped, nor is it tender. The exquisite tenderness
and patient education. There was moderate evidence
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Figure 1 This image shows how a taut band in the upper trapezius fibres is palpated and fixed to allow safedry needling of the trigger point with an acupuncture needle.
The taut band is the primary identifiable abnormality
times that of normal end plate potential discharges.
accessible to physical examination in the muscle,
They are likely to occur as the result of an abnormally
and may be present without tenderness. However,
excessive, spontaneous release of acetylcholine from
tenderness in MPS is not present without a taut band.
the synaptic terminal of the motor nerve fibre. This
The clinical diagnosis is made by physical
has not been proven, however. The taut band has the
characteristic that when it is stimulated mechanically
Identification of the trigger point by physical
it contracts sharply. Mechanical stimulation, either by
examination has good inter-rater reliability.20 A
strumming the taut band or by needling it, results in
characteristic electromyographic discharge termed
a mechanical deformation of the band. A sharp
spontaneous electrical activity (SEA) is associated
contraction of the muscle in response to needling is
with the taut band. The term SEA has been replaced
seen on electromyographic recordings as a high
by the more accurate term ‘end plate noise’. Low
amplitude (1-2mV) polyphasic discharge of up to
amplitude (10-50PV) discharges are present in the
250 milliseconds duration. It is maximally elicited
taut band, whether painful or not. Intermittent high
from the most tender region of the taut band,
amplitude (up to 500PV) discharges are seen in
diminishes with increasing distance from that point,
painful trigger points. The electrical discharges have
and is not elicited when recording from normal
the characteristics of miniature end plate potentials
muscle as little as 10mm from the taut band. Endplate
except that they occur with a frequency that is 10-100
noise is reduced by as much as 22% by the infusion
of phentolamine – an alpha 2 presynaptic blocker
that inhibits adrenergic sympathetic activity.21
Table 2 Essential diagnostic features of myofascial pain
Phentolamine causes an increase in the release of
norepinephrine into the synapse by blocking the
tenderness in the hardened or taut band of muscle
norepinephrine. Beta adrenergic receptors can be
reproduction of usual or spontaneous pain
stimulated by this action, as for example in the heart.
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Thus, the abnormal spontaneous electrical activity
Table 3 Causes of persistent myalgia
associated with the taut band is modulated by the
sympathetic nervous system, most likely by activity
Category
of adrenoreceptors on the motor nerve terminal.
The sensory abnormality is that of muscle
tenderness, felt as both local and referred pain.
Experimental models of muscle pain demonstrate
that central sensitisation occurs in response to noxious
stimulation in the presence of a persistent irritating
stimulus, such as an injection of bradykinin into the
muscle. This results in lowering the threshold for
pain and increasing the number and size of the
receptive fields to which a single dorsal horn
nociceptive neuron responds (Mense et al Muscle
spinal curvature, and to level the eyes with the
Pain p 84-98).18 In the human, this is expressed as
horizon. The shoulder and neck muscles must level
hypersensitivity or allodynia, manifest as tenderness,
the head. Chronic muscle contraction to bring the
spontaneous pain, or referred pain. The relationship
spine back to the midline can produce trigger points
between the taut band and pain is explained by the
and myofascial pain. Thus, a local or regional
integrated hypothesis of Simons (Mense et al Muscle
myofascial syndrome can spread through the body
Pain p 252-7).18 In this hypothesis, an excess release
and become a widespread myofascial syndrome
of acetylcholine at the motor end-plate results in the
creation of taut bands in the affected muscle that
compress capillaries thereby decreasing local blood
Non-structural perpetuating factors
flow and causing ischemia. Ischemia limits the
Medical factors that result in neurological functional
availability of oxygen and glucose, thereby creating
impairment include vitamin B12, other vitamin
an energy crisis in the working muscle. As a result,
insufficiency states, iron insufficiency, thyroid
potassium, histamine, substance P and other
deficiency states, and chronic infections, such as
excitatory substances that activate peripheral nerve
Lyme disease, and recurrent Candida albicans
nociceptive receptors are released, stimulating dorsal
horn nociceptive neurons and causing pain.
Vitamin B12 deficiency is a common problem
Myofascial pain spreads through the involvement
that affects an increasing percentage of persons over
of functional muscle units, or muscles that work
the age of 65 because the synthesis of intrinsic factor
together either as agonists or antagonists. An MTrP
decreases with age. As many as 15-20% of persons
restricts the range of motion related to a specific
over the age of 65 are estimated to be deficient.22;23
muscle, and weakens the muscle. Compensation for
Moreover, the pathways of absorption and utilisation
the impaired function of the muscle loads other
are complex and there are many mutations that can
muscles in the functional unit. For example, if the
occur that reduce absorption or metabolic activity.
upper trapezius muscle is impaired because of
Folic acid corrects the anaemia of B12 deficiency,
myofascial trigger points, the levator scapulae muscle
but not the neuromuscular deficit. Thus, pernicious
will be overloaded in controlling scapular motion,
anaemia is a marker of B12 deficiency, but is not
and the posterior cervical muscles like the
adequate alone because B12 deficiency exists in the
semispinalis capitis will be overloaded in extending
absence of anaemia. The non-haematological
the neck. Myofascial pain can also spread through
manifestation of B12 deficiency is nerve dysfunction
axial dysfunction. Trigger points in the psoas or
in the brain (cognitive impairment), the spinal cord
quadratus lumborum muscles can produce a pelvic tilt
(combined degeneration of the cord), and in the
that looks like a leg-length inequality, causing
peripheral nerve (neuropathy). It is likely that the
scoliosis. Shoulder tilt occurs to accommodate the
peripheral neuropathy is linked to the diffuse myalgia
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that is sometimes seen in B12 deficiency and that
25ng/ml in 60% of cases, and below 50ng/ml in 83%
improves with B12 replacement. If serum B12
of cases studied.26 This suggests that not only are
concentration is below 300pg/ml, methylmalonic
serum ferritin levels below 20-25ng/ml clinically
acid and homocysteine are good markers for
significant in restless legs syndrome, but that levels
metabolic abnormalities caused by B12 insufficiency.
below 50ng/ml are possibly clinically significant and
However, there may be metabolic abnormalities of
likely to be suboptimal. One cannot make a direct
B12 function even in the absence of elevations of
relationship from these data to determine the optimal
levels of ferritin in the development of muscle pain,
Iron deficiency in muscle occurs when muscle
but this gives some general guidance as to what might
ferritin is depleted. This occurs at serum ferritin
be considered minimally optimal and suboptimal
levels of about 15ng/ml. The prevalence of iron
deficiency in females age 12-49 is 9-16%. It is higher
A deficiency of freely accessible iron in muscle
in African-Americans and Hispanics (19-22%). Iron
creates an energy crisis in muscle by limiting an
is essential for the generation of energy through the
energy producing reaction. In this way, iron
cytochrome oxidase enzyme system. Iron deficiency
deficiency can be a factor in the development or
causes fatigue, poor endurance and can cause muscle
maintenance of myofascial trigger points. Moreover,
pain. Replacement is available both by the oral and
with respect to the role that iron plays in contributing
to a sleep disorder through producing restless legs
Iron deficiency has been generally defined as a
syndrome, there is a connection between iron
level of iron that is associated with anaemia. Levels
deficiency, sleep deprivation and myalgia. Restless
vary with age and sex, falling in adolescence with
legs syndrome is associated with a sleep disturbance
increased growth and, in girls, with the onset of
or sleep deprivation, with reduced levels of, or
menstrual blood loss. Iron stores rise again in
absence of, deep sleep. Thus, iron insufficiency
adulthood, and again in post-menopausal women.
associated with restless legs syndrome can be
This variation is important in assessing iron stores as
indirectly also associated with myalgia.
a possible factor contributing to muscle pain,
particularly in adolescent girls and in pre-menopausal
musculoskeletal pain, loss of type II muscle fibres,
women. Iron stores are assessed best by measuring
and proximal muscle atrophy.27;28 Plotnikof and
serum ferritin. Anaemia is associated with ferritin
Quigley found that 89% of subjects with chronic
levels below 10ng/ml.24 However, iron loss as
musculoskeletal pain were deficient in Vitamin D.29
determined by low ferritin levels does not correlate
The diagnosis was made by measuring 25-OH
directly with anaemia. The first stage of iron loss is
vitamin D. Values above 20ng/ml were considered
associated with depletion of freely accessible iron
normal. However, other studies suggest that levels
stores in muscle, liver and bone marrow when the
below 34ng/ml represent vitamin D deficiency.
serum ferritin level is about 15ng/ml. The second
Vitamin D deficiency is easily detected by measuring
stage of iron deficiency is erythrocyte microcytosis
25-OH vitamin D. The deficiency state is easily
without anaemia. The third stage is anaemia, by
corrected, but it takes up to six months of replacement
which time iron bone marrow stores are undetectable.
to reverse changes caused by deficiency states. People
Symptoms such as chronic tiredness, unusual fatigue
not exposed to the sun are at great risk, including
with exercise, and coldness begin with the first stage
those whose clothes leave little skin exposed to the
of iron loss. Optimum ferritin levels are unknown
sun, and those who spend little time out of doors.
for normal muscle function, but Sun et al reported that
in restless leg syndrome, another condition
aggravated by iron deficiency or in some cases caused
by it, serum ferritin levels below 50ng/ml were
Observations of patients with chronic myalgia
associated with a worsening of restless legs
suggest that hypothyroidism is causally linked to this
syndrome.25 In this same condition, but in adolescents
condition. There is some evidence to support thyroid
and children under the age of 18, the serum ferritin
dysfunction in FMS, but little epidemiological
level was below 20ng/ml in 50% of cases, below
evidence to confirm the clinical impression that thyroid
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dysfunction is associated with chronic myofascial
of T3 is a factor that causes chronic muscle pain such
pain syndrome. However, the absence of such data
as FMS.32;33 Specifically, the issue is whether reverse
may lie in flaws in the studies themselves.
T3 blocks the effect of T3 at the cellular level, thereby
Underactive thyroid function is a form of
creating a peripheral hypothyroidism unrelated to
hypometabolism. It can occur as a result of
hypothalamic or thyroid gland function. There are
insufficient production of T4, either because of
conflicting data regarding the metabolic activity of
insufficient secretion of thyroid releasing hormone
rT3, and its action as an inhibitor of T3, capable of
(TRH) as a result of a lack of hypothalamic
producing a hypometabolic state. Another view is
responsiveness, or because of thyroid disease itself,
that rT3 is metabolically inactive, but is a marker
such as Hashimoto’s thyroiditis. It also occurs
for down regulation of the thyroid axis. In this
because of impaired conversion of T4 to T3.
situation, elevation of rT3 signals an impairment of
Conversion of inactive to active thyroid hormone is
the feedback mechanism in which TSH rises when T3
the result of 5’-deiodination of T4 and occurs in the
concentrations fall. These issues are important in
liver.30 Peripheral suppression of thyroid hormone
both MPS and FMS, because there are reasons to
activity also occurs in ‘non-thyroidal illness
believe that rT3 is increased in both conditions.
syndrome’ (previously call the ‘sick euthyroid
syndrome’). Acute and chronic stress also affects the
b) Hypothyroidism and chronic and critical
hypothalamic-pituitary-adrenal axis, which may in
turn have several different effects on thyroid function.
Clinical hypothyroidism with normal levels of
These effects include suppression of thyroid
T3, T4 and TSH occurs in the so-called sick euthyroid
stimulating hormone (TSH) resulting in decreased
state often seen in chronic illness or in the Intensive
release of T4 from the thyroid gland, and inhibition
Care Unit in prolonged critical illness. This condition,
of 5’-deiodinase I, thereby decreasing the peripheral
also known as non-thyroidal illness, has bearing on
conversion of inactive T4 to active T3.31 In addition,
the postulated hypothyroid hypometabolic state of
reverse T3 (rT3) is increased, at least in the acute
FMS, with normal laboratory parameters of thyroid
stress response. Chronic stress can also result in
function (TSH, T3, T4). This issue has not been
hypoactivation or suppression of the hypothalamo-
addressed so directly in MPS, but if both MPS and
pituitary-adrenal axis, causing a decrease in cortisol
FMS, when chronic, have a similar underlying basis
releasing hormone (CRH). This in turn results in the
of central hypersensitivity, and if both are initiated by
decrease in glucocorticoid production and a
an acute or recurring energy crisis, then a postulated
secondary increase in auto-immune disorders such as
hypothyroid hypometabolic state becomes relevant
The relationship of hypothyroidism to muscle
Tissue thyroid levels are reduced in prolonged
pain is complex because there is a controversy over
critical illness. Evidence suggests that there is a central
the mechanism of so-called hormone resistant
neuro-endocrine failure, at least in part at the level of
hypothyroidism due to peripheral blocking of T3
activity, and over its relationship to the development
responsiveness to other factors such as growth
of myalgia. Few would argue about whether
hormone.34 On the other hand, non-thyroidal illness
hypothyroidism associated with an elevated TSH
syndrome with low levels of T3 and T4 can be an
should be treated. In normal individuals whose TSH
acute response to stress. Possible causes of this
levels are under two units, slight elevations of the
phenomenon range from a decrease in the deiodination
TSH often indicate mild hypothyroidism. These
of tetra-iodothyroxine by 5’-deiodinase to make tri-
patients often complain of fatigue, feel cold, tend to
iodothyroxine, inhibition of T4 and T3 binding
be constipated, have dry skin, and muscle pain.
proteins, or the action of circulating cytokines. A study
Treatment with a thyroid supplement that reduces
of healthy individuals undergoing elective abdominal
the TSH level to 1.5 units or less will often improve
surgery explored the response of thyroid function to
these symptoms, and render the muscle more
acute stress. There was a decline of T3 starting 30
responsive to treatment. A controversy exists over
minutes before the skin incision was made that
whether hypothyroidism responsive to large doses
continued throughout the postoperative observation
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period. An early rise in TSH attenuated the decline
This question of the role of rT3 has been looked at in
of T3 after eight hours. T4 rose soon after the skin
non-myalgic illness. Reverse T3 has been shown to
incision and remained elevated. Reverse T3 rose six
be a marker for increased mortality after acute
hours after surgery and remained elevated. Serum
myocardial infarction.38 T3 was slightly reduced in
cortisol levels rose rapidly after entering the operating
suite and remained high thereafter. Cytokine responses
considerably increased, and T4 was slightly
were mixed, interleukin-6 (IL-6) rising two hours
increased, signifying reduced conversion of T4 to
after skin incision and tumour necrosis factor alpha
T3. TSH was slightly lower in the MI patients than
(TNF-1 alpha) not rising at all. The rapid rise in
in the controls. However, only the increased levels of
cortisol was hypothesised to cause the fall in T3 in
rT3 and T4 correlated with increased mortality.
this acute syndrome.35 In another study of the euthyroid
Despite reports that intravenous T3 was beneficial in
sick syndrome that was created experimentally by
animal studies of myocardial infarction, T3
isolated limb perfusion with TNF-alpha, there was a
administration to patients undergoing cardiac bypass
rapid fall in T3, rT3, T4 and thyroxine-binding
surgery did not improve outcome.38 The authors
globulin (TBG), whereas free T4 (fT4) showed a
speculated that rT3, usually considered to be an
sharp rise. T3 remained low, but rT3 rose over 24
inactive metabolite, has biologic activity, perhaps
hours. TSH declined initially, but rose progressively
to greater than pre-perfusion levels and remained
On the other hand, a study correlating molecular
elevated over one week. Cortisol or IL-6 was thought
modelling of thyroid hormone metabolites with the
to be related to the decline in T3 and T4 levels.
known inhibition of gamma-aminobutyric acidA
Recovery was thought to be TSH dependent, because
(GABAA) by T3 showed only a weak effect of rT3,
its rise preceded the rise of T4 and T3.36 Thus, in the
and made the point that the molecular configuration
sick euthyroid syndrome, the decline in T3 function
of rT3 was less rigid than native T3, so that there is
appears to be related to an initial fall in T3 levels, and
greater flexibility between the two aromatic rings,
a decline in the conversion of T4 to T3, and might be
thereby affecting ion channel activity and GABAA
a response to a rise in cortisol levels.
activity.39 This study suggests that rT3 is biologically
inactive at least some of the time. Finally, it is thought
that in inflammatory stress conditions, cytokines can
The role of rT3 in non-thyroidal illness remains
unclear. Changes in rT3 may be a marker of non-
The question of the relationship of the factors
specific response to acute or chronic stress. For
that produce a hypometabolic state to chronic myalgia
example, rT3 was elevated in females with ankylosing
as a result of stress will now be addressed.
spondylitis, whereas FT3 and FT4 and total T3 were
Hypothalamic-pituitary-adrenal axis response to
significantly lower. TSH and total T4 were normal.
stress has been well studied in the acute stress state.
Antithyroid antibodies were elevated as well.37 TSH
Disorders of this axis have been implicated in the
response to thyrotropin releasing hormone (TRH)
development of FMS.13 The acute state is associated
was normal. It was not stated in this study whether
with activation of the hypothalamic-pituitary-adrenal
the AS subjects were clinically hypothyroid. The
axis and an increase in CRH. Glucocorticoids are
controversy is whether rT3 is metabolically active or
increased, suppressing the immune system, and by a
not, and if it is an inhibitor of T3, thereby producing
feedback mechanism, lead to termination of the acute
a hypometabolic state. The alternative view is that
stress response. Moreover, glucocorticoids also
rT3 is metabolically inactive, but is a marker for down-
decrease growth hormone secretion and inhibit
regulation of the thyroid axis as illustrated in the above
somatomedin C, both phenomena known to occur
study. In this view, elevation of rT3 indicates that the
in FMS, but not really well studied in MPS. The
feedback mechanism in which TSH rises in response
adrenergic system (locus coeruleus-norepinephrine
to lowering of T3 is impaired. This controversy is
system) is also activated. Release of beta-endorphins
important in both MPS and FMS, because there are
from the hypothalamus in the acute stress response
reasons to believe that rT3 is increased in both
suppresses pain perception. Activation of the
hypothalamic-pituitary-adrenal system also centrally
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suppress TSH production and inhibit the peripheral
that nearly 10% of Caucasians had FMS, about 2-3
conversion of T4 to T3, producing the non-thyroidal
times the expected prevalence in the general
illness syndrome. Cytokines are potent activators of
population. The prevalence was much lower in
the stress response. Tumour necrosis factor alpha
African-Americans and in Hispanics, with an overall
(TNF-alpha), IL-6 and interleukin 1 alpha are known
prevalence of 5%, a little more than has been reported
to stimulate the hypothalamic-pituitary-adrenal
in general studies (2-4% prevalence in various
system. They have also been implicated in inhibiting
studies). FM correlated best with Caucasian ethnicity,
anxiety, or affective disorder. It did not correlate with
As suggested by the above studies, rT3 elevation
SLE clinical activity, specific organ damage, or
is a non-specific response to both chronic illness and
serologic features.4 Thus, SLE is appropriately
acute stress. The question remains unanswered
considered in the Caucasian sub-population of FMS
whether rT3 is functioning as a blocker to the action
patients. However, it is unknown in how many SLE
of T3 by competing for T2 receptors at the cellular
patients SLE is the presenting manifestation.
level, resulting in hypothyroidism, and whether such
Moreover, the course of FMS and SLE do not seem
an effect, if present, can be overcome by increasing
TSH levels or by T3 supplementation.
Finally, the relation of chronic infection to
myalgia (both MPS and FMS) is interesting. The
investigation of specific conditions is warranted when
the history is compatible with such a diagnosis. This
associated with FMS. Measurements of insulin-like
concept was dramatically illustrated in a competitive
growth factor-1 (IGF-1) show a deficiency in about
athlete who swam in ponds and lakes throughout the
30% of FMS patients.42 GH deficiency syndromes
United States over a period of time. This athlete
share many characteristics with FMS. GH secretion
complained of fatigue and diffuse muscle pain. Two
may be impaired secondary to a variety of physical
protozoan infections, including amoebiasis, and Lyme
and psychological stressors. It is a treatable condition,
disease were found. Chronic Lyme disease was the
and therefore worth investigating in FMS who do
specific factor causing muscle pain and fatigue.
not have other identifiable causes or co-morbidities.
Common considerations in the United States include
Whether patients with FMS and GH deficiency have
parasitic infections, Lyme disease, chronic
one disease (GH deficiency), or have FMS made
mycoplasma infections, and enteroviruses.
worse by GH deficiency, is a moot point. The point
made by Bennett is that treatment with GH results in
combination of myalgia and arthralgia, fatigue and
clinical improvement.42 However, a study of
impaired cognition, all features seen with FMS.
premenopausal women showed no association
Treatment of such persons is difficult. The chronic
between FMS and IGF-1 casting doubt on the validity
state, sometimes referred to as Post-Lyme disease
of this association in this age group.43 The authors
syndrome or Post-treatment Lyme disease syndrome,
point out that older age and obese populations have
failed to show an improvement in cognition, but did
lower activity of the GH-IGF-1 axis, and that these
show improvement in fatigue, after prolonged
conditions must be considered when studying the
treatment with either 30 days intravenous ceftriaxone
GH-IGF-1 axis in FMS subjects. Thus, it can be said
followed by oral doxycycline, or 28 days of
that GH deficiency produces a syndrome much like
intravenous ceftriaxone.45;46 However, macrolide
FMS, but it is far from clear whether a subset of
antibiotics are less active at acidic pH, and poor
FMS patients can be said to have FMS as a result of
responses such as those just cited, may be due to
impaired GH secretion. Moreover, the sub-
localisation of the spirochete in an acidic endosome.
populations of FMS patients where this might apply
Macrolide antibiotic activity, but not that of the
tetracyclines, may be enhanced by alkalinisation
with hydroxycholoquine.47 Other diseases that look
like Lyme disease, but that are treated differently,
A study of the connective tissue disorder systemic
like Babesiosis and Ehrlichiosis, should also be
lupus erythematosis (SLE) and fibromyalgia showed
considered in persistent and difficult cases.
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Enterovirus infection has been investigated in FMS
are necessary to identify metabolic, hormonal or
and chronic fatigue syndrome (CFS) patients by
nutritional disorders that are important in chronic
polymerase chain reaction (PCR) assays of muscle
myalgia. Depending on the direction of investigation
biopsy tissue. A number of studies have shown a
suggested by the history and physical examination,
significant increase in the prevalence of PCR positive
the laboratory tests in Table 4 are useful in the
samples for enterovirus, and positive neutralising
evaluation of chronic myalgia, including both MPS
antibody for Coxsackie B virus, in patients with chronic
and FMS. Generalised or widespread muscle pain is
fatigue syndrome, ranging for 20% to 58%, compared
more likely to be metabolic, whereas structural or
to controls showing 0-9% positive.48;49 In one study of
mechanical factors are often seen with focal myalgias.
FMS patients, 13% (4 out of 30) were positive for
The exception is hypermobility syndromes that can be
enterovirus, compared to none of 29 controls.50
associated with generalised MPS. Iron insufficiency
However, another study failed to show evidence to
is usually restricted to women, and is generally seen
support a role of persistent enteroviral infection in
in men only when there has been gastrointestinal
CFS patients, but could not exclude the possibility of
blood loss from ulcers or cancer, or from taking non-
such an infection being an initiating factor.51 This is
steroidal anti-inflammatory drugs. Vitamin B12
an interesting etiologic consideration, but as of now, of
deficiency is far more prevalent than one might think,
little practical clinical use, since muscle biopsy is not
and approaches 15 percent of persons with chronic
routinely done in FMS patients, and there is no specific
MPS. Metabolic abnormalities can be seen at levels
treatment for enterovirus infection.
as high as 350pg/ml. Folic acid metabolism is closely
linked to that of vitamin B12, and should also be
measured. Other vitamin deficiency states such as
The history gives clues about structural and metabolic
vitamin C and vitamins B1 and B6 can also be
or nutritional problems that lead to further, focused
associated with widespread myalgia. Vitamin D levels
examinations. The physical examination is the place
below 32pg/ml have been found to be associated
to look for scoliosis, leg length inequality, pelvic
with musculoskeletal pain. Hypothyroidism is a major
torsion, and hypomobility and hypermobility of joints.
consideration because it produces a hypometabolic
Imaging studies are often not necessary for this
state thought to promote trigger point formation.
purpose, though they play an important role in
Values of thyroid stimulating hormone (TSH) in the
identifying co-morbid conditions. Laboratory tests
upper half of the normal range (above 2.5
Table 4 Laboratory investigations for chronic FMS and MPSinvestigation
tissue stores are depleted at levels of 15-20ng/ml
impairment at levels as high as 350pg/ml. Follow-up testing includes serum methylmalonic acid and homocysteine.Either may be elevated in vitamin B12 deficiency
folic acid metabolism is closely linked to vitamin B12 action
normally generally below 2.5 ISU. Careful history and physical examination often show signs of hypothyroidism inpersons whose TSH level is in the upper normal range
levels below 32ng/ml are seen in symptomatic individuals
ELISA confirmed by Western blot. Also test for Ehrlichiosis, Babesiosis and Bartonella – may simulate Lyme Disease or co-exist with it
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international standard units) should lead to careful
needle is inserted into subcutaneous tissues about
evaluation of possible clinical hypothyroidism.
4mm overlying the trigger point, is another means
Infectious diseases can cause widespread pain,
whereby the myofascial trigger point can be
particularly Lyme disease. Hepatitis C has been
inactivated.54;55 Acupuncture has also been used to
associated with fibromyalgia. Connective tissue
treat myofascial pain syndrome. There are few
diseases such as lupus erythematosus have also been
controlled or blinded studies to rely upon. However,
there is some indication that acupuncture may be
effective in treating some myofascial pain
Treatment of myofascial pain requires the inactivation
of MTrPs, the restoration of normal muscle length,
stresses that may cause or aggravate trigger point
and the elimination or correction of the factors that
formation and activation must also be addressed and
created or perpetuated the trigger points in the first
corrected or alleviated. Once trigger point pain is
place. Manual therapy to do this includes trigger
reduced and perpetuating factors are addressed, a
point compression, often accompanied by a short
physical conditioning programme can strengthen
excursion of the appropriate body part actively to
muscle, increase endurance, and perhaps reduce the
slightly lengthen and shorten the muscle. MTrP pain
possibility of reactivating the trigger points.
will usually subside within 20-30 seconds, the
referred pain will disappear, and finally the taut band
Conclusion
will relax, if not go away, within about a minute.
Patients with myalgia can have many co-morbid
The taut band of muscle is stretched locally along
conditions that perpetuate or aggravate their muscle
its long axis for a distance of a few inches. This local
pain. Such conditions may cause myalgia in the first
stretch is not across a joint. A myofascial release
place, or interfere with the recovery or treatment
technique is applied to the muscle to stretch the fascia,
process. Identification of such conditions should be
moving over the skin away from the trigger point.
undertaken in all chronic cases of myalgia. In some
A larger range therapeutic stretch is applied, to stretch
cases, an obvious structural abnormality can be
the muscle across the joint or joints associated with
identified by physical examination. In other cases,
the muscle, e.g. the hip and knee for the rectus
detailed history-taking and laboratory examination
femoris muscle. These stretches must be muscle
may be required. Multiple co-morbidities are not
uncommon, particularly the combination of a
MTrPs can also be inactivated by inserting a
structural imbalance and a medical condition.
needle into the trigger zone or point (Figure 1). This
can be done with or without the injection of local
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recognize the anatomical heart in all itsthem facts and figures and knowledge. we would have to doubt this statement. study, is nobody’s heart. It is a heartfrom the Middle English, to recognize . mental health related disciplines are re-specific field of knowledge. They are re-heart; the heartless one; the cold heart;dents are not required to seek wisdom. and idein which means to se